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Clinical and Forensic Toxicology. Roger L. Bertholf, Ph.D. Associate Professor of Pathology Chief of Clinical Chemistry & Toxicology. Toxicology Disciplines. Industrial Toxicology Toxic exposures in the workplace Product testing Molecular Toxicology Veterinary Toxicology

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clinical and forensic toxicology

Clinical and Forensic Toxicology

Roger L. Bertholf, Ph.D.

Associate Professor of Pathology

Chief of Clinical Chemistry & Toxicology

toxicology disciplines
Toxicology Disciplines
  • Industrial Toxicology
    • Toxic exposures in the workplace
    • Product testing
  • Molecular Toxicology
  • Veterinary Toxicology
  • Environmental Toxicology
  • Clinical Toxicology
  • Forensic Toxicology
clinical toxicology
Clinical Toxicology
  • The branch of toxicology that is concerned with human poisoning
    • Drug overdoses
      • Pharmaceuticals
      • Drugs of abuse
    • Toxic exposures
      • Environmental
      • Occupational
      • Accidental
the top ten poisoning
The Top Ten Poisoning. . .

Exposures

Deaths

  • Cleaning Products
  • Analgesics
  • Cosmetics
  • Plants
  • Cough/Cold Preparations
  • Hydrocarbons
  • Bites
  • Topicals
  • Foreign Bodies
  • Chemicals
  • Antidepressants
  • Analgesics
  • Sedative/Hypnotics
  • Street Drugs
  • Cardiovascular Drugs
  • Alcohols
  • Fumes
  • Chemicals
  • Asthma Medications
  • Cleaning Products
pharmacokinetics
Pharmacokinetics

Peak plasma concentration

Plasma drug concentration

t1/2

Time 

the autonomic nervous system
The Autonomic Nervous System

Sympathetic

(Thoracocolumbar)

Norepinephrine

Parasympathetic

(Craniosacral)

Acetylcholine

Muscarinic

Nicotinic

GI

Vascular smooth

muscle

1

2

Cardiovascular

Smooth muscle

Insulin release

Gluconeogenesis

cholinergic poisoning
Cholinergic Poisoning
  • Organophosphates, some mushrooms (Group III, clytocybe and inocybe species), betel nuts, pilocarpine, carbachol, acetylcholine
  • Miosis, vasodilatation, bronchial secretions, bradycardia, increased bowel motility, urination, sweating
  • Mnemonic: DUMB BELS (Diarrhea, Urination, Miosis, Bradycardia, Bronchorrhea, Emesis, Lacrimation, Salivation)
  • Atropine + pralidoxamine is antidote
  • Laboratory monitors AChE activity
anticholinergic poisoning
Anticholinergic Poisoning
  • Belladonna, Jimsonweed, antihistamines, phenothiazines, certain mushrooms (Group V), scopolamine, tricylics, OTC sleeping pills
  • Mnemonic: Red as a beet, dry as a bone, mad as a hatter, hot as a stone, bowel and bladder lose their tone, and the heart runs alone.
  • Physostigmine is antidote
sympathetic poisoning
Sympathetic Poisoning
  • : vasoconstriction, pupillary dilitation, coronary artery dilitation, decreased bowel motility, bladdar contraction
  • 1: tachycardia
  • 2: smooth muscle dilatation, insulin release, lipolysis, renin release, gluconeogenesis (miosis, vasodilatation, bronchodilatation, hyperglycemia, decreased bowel motility, bladder relaxation)
nicotinic poisoning
Nicotinic Poisoning
  • Insecticides, tobacco, black widow spider venom
  • Tachycardia, hypertension, muscle fasciculations, weakness, paralysis
  • d-turbocurarine is antidote
ethanol
Ethanol
  • Most common (by far) toxic exposure
  • Often associated with:
    • Trauma
    • Loss of consciousness
    • Other drug exposure
  • Frequently involves medico-legal interventions
ethanol pharmacodynamics
Ethanol Pharmacodynamics

Loss of consciousness

Staggering gait

CNS impairment 

Slurred speech

Blood alcohol concentration (mg/dL, %)

Impaired motor coordination

Loss of inhibition

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

ethanol distribution
Ethanol distribution

Cells

82% H2O

Serum

95% H2O

EtOH

Serum (or plasma) ethanol is 5 – 15% higher than whole blood ethanol

enzymatic ethanol methods
Enzymatic Ethanol Methods
  • ADH is selective, but not specific for ethanol
  • Other enzymes that involve NADH can potentially interfere
non ethanol alcohol poisoning
Non-ethanol Alcohol Poisoning
  • Alcohol toxicity is primarily related to metabolites
    • Ethanol  Acetaldehyde  Acetate
    • Isopropanol  Acetone
    • Methanol  Formaldehyde  Formic acid
    • Ethylene Glycol  Oxalate and Hippuric acid
  • Non-ethanol alcohol exposures can be detected by an increase in the osmol gap
the osmol gap
The Osmol Gap

Calculated Osmolality:

the osmol gap20
The Osmol Gap
  • Colligative properties depend on the number of of dissolved particles
    • Boiling point
    • Freezing point
  • Osmolality is usually determined by freezing point depression
  • The difference between the calculated and measured osmolality is the Osmol Gap
osmol gap mnemonic
Osmol Gap Mnemonic

Methanol

Ethanol

Diuretics (glycerol, mannitol, sorbitol)

Isopropanol

Ethylene glycol

analgesic poisoning
Analgesic Poisoning

Exposures

Fatalities

salicylate poisoning
Salicylate Poisoning
  • Toxic symptoms develop at serum concentrations exceeding 250 mg/L
  • Serum concentrations exceeding 1000 mg/L can be fatal
  • Symptoms are tinnitus, hyperventilation, respiratory failure, convulsions, coma
  • Lab results reveal mixed metabolic acidosis/respiratory alkalosis
  • Acidification of urine enhances elimination
acetaminophen poisoning
Acetaminophen Poisoning
  • Toxic symptoms develop at serum concentrations exceeding 100 mg/L
  • Serum concentrations exceeding 450-500 mg/L result in severe liver damage
  • Symptoms may not appear until hepatic failure is evident and irreversible
  • Antidote is N-acetylcysteine
carbon monoxide poisoning
Carbon Monoxide Poisoning
  • Can be deliberate or accidental
    • CO is odorless
  • CO binds irreversibly to hemoglobin, displacing oxygen
  • CO-Hb (carboxyhemoglobin) can be measured on a co-oximeter
    • Different max than O2-Hb (oxyhemoglobin)
  • Hyperbaric oxygen may be indicated
metal poisonings
Metal Poisonings
  • Iron is most common (particularly in kids)
    • Ferritin
    • Deferoxamine is antidote
  • Arsenic is most notorious
    • Acute vs. chronic
    • Inorganic vs. arsine gas
    • BAL (dimercaprol) is antidote
metal poisonings29
Metal Poisonings
  • Lead
    • Most cases in children exposed to lead paint
    • Blood lead >10 g/L is considered risk
    • Monitor with -aminolevulinic acid dehydratase
    • EDTA is antidote
  • Mercury
    • Organic vs. inorganic
    • Neurotoxic, nephrotoxic, teratogenic
spot tests for metal poisoning
Spot Tests for Metal Poisoning
  • Reinsch Test: Copper wire turns. . .
    • Shiny silver: Mercury
    • Dull black: Arsenic
    • Shiny black: Bismuth
    • Dark purple sheen: Antimony
  • Gutzeit test for arsenic
    • Acidification produces arsine gas, which discolors silver nitrate paper
  • Iron reacts with potassium ferricyanide and ferrous sulfate to produce Prussian Blue
tlc stains
TLC Stains
  • Ninhydrin: 1o or 2o amines (sympathomimetics)
  • Mercuric Sulfate: barbiturates, glutethimide, phenytoin (white ppt)
  • Diphenylcarbazone: same as mercuric sulfate (blue or purple spot)
  • Iodoplatinate: 3o amines
  • Dragendorf's reagent: methaqualone
  • UV absorption at 254 nm: benzodiazepines, barbiturates, methaqualone
  • Fluorescence at 366: Benzodiazepines, quinine, quinidine
medical vs forensic drug testing
Patient consent not required

Identity of specimen is presumed

Screening result is sufficient for medical decision

Results are used for medical evaluation

Subject must consent to be tested

Identity of specimen must be proved

Only confirmed results can be considered positive

Results are used for legal action

Medical vs. forensic drug testing
illegal drug use in the u s 1998 household survey
Illegal Drug Use in the U.S.(1998 Household Survey)
  • 13.6 million Americans use illicit drugs
    • 25 million in 1979
  • 8.3% of youths age 12-17 use marijuana
    • 14.2% in 1979
  • 1.8 million Americans use cocaine
    • 5.7 million in 1985
history of workplace drug testing
History of workplace drug testing
  • 1960s – 1970s: The Department of Defense begins testing military personnel for illegal drug use.
  • 1986: President Reagan establishes the “Federal Drug-Free Workplace”.
  • 1988: Mandatory Guidelines for Federal Workplace Drug Testing Programs is published in the Federal Register.
the nida program
The “NIDA” program
  • NIDA (now SAMHSA) requirements for drug testing were drafted by Research Triangle Institute
  • The RTI established the National Laboratory Certification Program (NLCP)
  • Drug testing for federal agencies (DOT, NRC, etc.) must be performed in a NLCP-certified laboratory
florida drug free workplace
Florida Drug-Free Workplace
  • The Florida HRS (now AHCA) established a drug-free workplace program in 1990
  • Specifications for the State of Florida program are similar to federal requirements, but there are notable differences
  • Employees of Florida Drug-Free Workplace-compliant businesses must be tested in AHCA-licensed laboratories
screening vs confirmation
Low cost

Fast

Semi-quantitative

High sensitivity

Low specificity

High cost

Slow

Quantitative

High sensitivity

High specificity

Screening vs. Confirmation
a confirmatory method should
A confirmatory method should . . .
  • Utilize the most accurate (specific) testing method available
  • Have sensitivity equal to or better than the screening method
  • Be economically feasible
  • Be simple enough to standardize across many laboratories
  • Produce results that are legally defensible
gc mass spectrometry
GC/Mass Spectrometry

Detector

Injector

Ionizer

Mass Filter

GC Column

Data System

electron impact ionization

Focusing

lens

From GC

+

+

To MS

+

Ion volume

(or source)

(-)

Electron impact ionization

Power supply

Filament

e-

e-

Collector

(+)

electron multiplier

From mass filter

e-

104 e-

+

Ammeter

Electron multiplier

Negative dynode

Positive dynode

cocaine
Cocaine

C17H21NO4

MW=303.35

slide50

82 (base peak)

182 [M-121]+

303 (M+)

121

[M-31]+ 272

slide52

82 (base peak)

182 [M-121]+

303 (M+)

121

[M-31]+ 272

slide54

44

91

slide56

44

91

slide58

58

91

thc cooh detection

THC-COOH glucuronide (15%)

Hydrolysis

THC-COOH

BSTFA

TMS-THC-COOH

THC-COOH detection